What are the important drug interactions and monitoring recommendations for St. John’s wort (Hypericum perforatum)?

St. John's Wort Drug Interactions and Clinical Management

St. John's wort is a potent inducer of CYP3A4 and P-glycoprotein that significantly reduces plasma concentrations of numerous critical medications, making it contraindicated or requiring extreme caution with most prescription drugs. 1

Mechanism of Action

St. John's wort accelerates the metabolism and elimination of substrate drugs through CYP3A4 and P-gp induction, thereby reducing their therapeutic effectiveness and potentially causing treatment failure. 1 This enzymatic induction persists for several months after discontinuation due to the herb's long-lasting effects. 1

Absolute Contraindications

The following medications should never be combined with St. John's wort:

Cardiovascular Medications

• Ivabradine is specifically contraindicated due to reduced effectiveness 1
• Amiodarone can lead to life-threatening arrhythmias when combined with St. John's wort 1
• Warfarin should be avoided due to risk of reduced anticoagulant effect and potential thrombotic complications 1

Antidepressants

• SSRIs and MAOIs are contraindicated due to risk of serotonin syndrome 1
• Monitoring for 24-48 hours after discontinuing St. John's wort is required, as serotonin syndrome symptoms can emerge during this period 1

Antiviral Medications

• HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors have significantly decreased plasma concentrations with St. John's wort 1
• Sofosbuvir and sofosbuvir/velpatasvir are contraindicated due to reduced drug exposure and potential hepatitis C treatment failure 1

Contraceptives

• Oral contraceptives have reduced effectiveness, leading to unintended pregnancies 1, 2
• The CDC categorizes this combination as Category 3 (risks generally outweigh benefits) 2

High-Risk Interactions Requiring Dose Adjustments or Alternative Therapy

Immunosuppressants

• Cyclosporine and tacrolimus concentrations are significantly affected, risking organ rejection 1, 3
• More frequent therapeutic drug monitoring is mandatory if combination cannot be avoided 1

Oncology Medications

• Imatinib plasma concentrations may be decreased, potentially requiring dose adjustments 1

Cardiovascular Medications

• Statins (atorvastatin, lovastatin, simvastatin) have significantly reduced levels due to CYP3A4 induction 1
• Digoxin levels are reduced through P-gp induction 1

Anticonvulsants

• Carbamazepine, phenytoin, and phenobarbital levels may be decreased 1

Safer Contraceptive Alternatives for Women Using St. John's Wort

If St. John's wort cannot be discontinued:

• Injectable depot medroxyprogesterone acetate (DMPA) is preferred as interactions with parenteral methods are less likely 2
• Intrauterine devices (IUDs) represent another effective alternative 2
• If oral contraceptives must be used, consider formulations with minimum 30 μg ethinyl estradiol plus an additional barrier method throughout the cycle 2
• Condoms provide additional protection against both pregnancy and STIs 2

Preoperative Management

Discontinue St. John's wort at least 2 weeks before surgery due to multiple potential drug interactions and effects on serotonin levels. 1, 4 This timeframe allows for partial resolution of enzymatic induction effects.

Clinical Monitoring Recommendations

When St. John's wort use is identified in patients on interacting medications:

• Obtain a complete herbal supplement history at every visit, as 31-68% of patients using supplements don't disclose this to physicians 4
• Monitor drug levels or therapeutic effects more frequently for all medications metabolized by CYP3A4 or transported by P-gp 1
• Ask specifically about hidden sources: mood/stress supplements, menopause products, herbal teas, and citrus beverage blends often contain St. John's wort without prominent labeling 4
• Use direct questions: "Do you take any supplements for mood, memory, sleep, or stress?" 4

Critical Pitfalls to Avoid

• Do not assume patients will volunteer supplement use – many don't consider supplements as "real medicine" and fail to report them 4
• Do not underestimate the duration of interaction – enzymatic effects persist for months after discontinuation 1
• Do not rely on product labels – St. John's wort is not FDA-regulated, with no standardization of content or potency 1
• Do not overlook photosensitivity risk – both St. John's wort and certain medications (like escitalopram) can cause photosensitive reactions 1

Documentation Requirements

• Provide written information about drugs to avoid and related medications that may cross-react 1
• Ensure all healthcare providers are informed about St. John's wort use to avoid potentially hazardous drug interactions 2
• Document the discussion about risks and alternative therapies in the medical record 1